The decline in adaptive immunity, T lymphocyte output and the contraction of the T cell receptor (TCR) repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of thymic progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic peptide hormone, ghrelin, and the anorexigenic hormone, leptin, are expressed by immune cells and regulate T-cell activation and inflammation. Our current work has demonstrated that both ghrelin and ghrelin receptor expression within the thymus diminishes with progressive aging. Infusion of ghrelin into old mice significantly improves the age-associated changes in thymic architecture and thymocyte counts with an increase in recent thymic emigrants (RTEs) and improvement of TCR diversity of peripheral CD4+ and CD8+ T cells. The ghrelin-induced thymopoiesis during aging was associated with enhancement of early thymocyte progenitors (ETP) and bone marrow-derived lineage negative sca-1, c-kit high (LSK) cell. Furthermore, the ghrelin and GHS-R deficient mice displayed enhanced age-associated thymic involution with reduced thymopoiesis and contraction of LSK hematopoietic stem cell compartment. The accelerated thymic involution observed in GHS-R knock out mice was reflected in major perturbations in the TCR repertoire of peripheral T lymphocyte subsets. Similarly, leptin infusion into old mice demonstrated similar effects on thymic progenitors and thymic involution as was observed with ghrelin and the pituitary hormone, growth hormone (GH); however, these anorexigen-induced changes appear to be mediated via distinct signaling pathways. Our findings demonstrate a novel role for these hormones and their receptors in thymic biology and suggest a possible therapeutic benefit of harnessing these hormonal pathways in reconstitution of thymic function in elderly and in immunocompromised subjects. Moreover, we have found that these hormones modulate a variety of leukocyte functions and support the existence of a functional immunoregulatory network involving orexigenic and anorexigenic hormones in controlling immune cellular activation and differentiation, hematopoiesis and cell survival.